It has been shown that membrane-located peptidases as, for example, DP IV or APN play a key role in the process of the activation and clonal expression of immune cells, particularly of T lymphocytes [Fleischer B: CD26 a surface protease involved in T cell activation. Immunology Today 1994; 15:180-184; Lendeckel U et al.: Role of alanyl aminopeptidase in growth and function of human T cells. International Journal of Molecular Medicine 1999; 4:17-27; Riemann D et al.: CD13—not just a marker in leukemia typing. Immunology Today 1999; 20:83-88]. Several functions of mitogen-stimulated mononuclear cells (MNC) or α-cumulated T lymphocytes as, for example, DNA synthesis production and secretion of immune-stimulating cytokines (IL-2, IL-6, IL-12, IFN-γ) and helper functions of B cells (synthesis of IgG and IgM) may be inhibited in the presence of specific inhibitors of DP IV and APN [Schön E et al.: The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes. Biomed. Biochim. Acta 1985; 2: K9-K15; Schön E et al.: The role of dipeptidyl peptidase IV in human T lymphocyte activation. Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro. Eur. J. Immunol. 1987; 17: 1821-1826; Reinhold D et al.: Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells. Immunology 1997; 91: 354-360; Lendeckel U et al.: Induction of the membrane alanyl aminopeptidase gene and surface expression in human T cells by mitogenic activation. Biochem. J. 1996; 319: 817-823; Kähne T et al.: Dipeptidyl peptidase IV: A cell surface peptidase involved in regulating T cell growth (Review). Int. J. Mol. Med. 1999; 4: 3-15; Lendeckel U et al.: Role of alanyl aminopeptidase in growth and function of human T cells (Review). Int. J. Mol. Med. 1999; 4: 17-27].
On the other hand, scientific discoveries of the recent years characterized arteriosclerosis as an inflammatory disease, whereby T lymphoctes play a decisive role in the development and progress of said disease [Ross R: Arteriosclerosis—an inflammatory disease. New England J. Med. 1999; 340 (2): 115-126]. According to those discoveries, arteriosclerotic lesions are understood as a series of specific cellular and molecular reactions which, when taken together, are to be characterized as inflammations, unequivocally. Such lesions primarily occurring in large and medium size elastic and muscular arteries result into ischemia (disturbed circulation) of the heart, of the cerebrum and of the extremities up to infarcts of the above-mentioned organs. Arteriosclerotic lesions are formed at defined arterial locations, where branches and curves effect characteristic changes of the blood flow and of the sheer stresses as well as the creation of turbulences [Gotlieb A I et al.: The role of rheology in atherosclerotic coronary artery disease. In: Fuster V, Ross R, Topol E J, eds. Atherosclerosis and coronary athery disease. Vol. 1 Philadelphia: Lippincott-Raven, 1996: 595-606]. Vessel endothel cells generate specific molecules at those locations, which molecules are responsible for the attraction, binding, accumulation and activation of T lymphocytes and monocytes. T lymphocytes are essential inflammatory cells in all phases of the arteriogenesis. T cells infiltrate from the peripheral blood into the arteriosclerotic plaques and multiply at the lesion location [Jonasson L et al.: Regional accumulation of T cells, macrophages and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986; 6: 131-138; van der Wal A C et al.: Atherosclerotic lesions in humans: in situ immunophenotypic analysis suggesting an immune mediated response. Lab. Invest. 1989; 61: 166-[70]. As a result of the accumulation, at the location of an arteriosclerotic lesion, of such activated T lymphocytes which are characterized by a strong expression of alanyl aminopeptidase and of dipeptidyl peptidase IV, chemokines, cytokines, growth factors and proteases are released, which compounds effect a further intensification of the disease conditions, as other immune cells are recruited and activated [Libby P and Ross R. Cytokines and growth regulatory molecules. In: Fuster V, Ross R, Topol E J, eds. Atherosclerosis and coronary athery disease. Vol. 1, Philadelphia: Lippincott-Raven, 1996: 585-594].
In addition, monocytes localized in arteriosclerotic plaques are characterized by the constitutive expression of, for example, alanyl aminopeptidase (APN). The same is true for endothelic cells which express those ectopeptidases, too.
The angiotensin-converting enzyme plays a particular role in the pathogenesis of arteriosclerosis. Said enzyme effects the generation of angiotensin II (ang II) from ang I, the former substance severely increasing the blood pressure. Hypertension is an important factor promoting the risk of arteriosclerosis, and patients suffering therefrom often have increased ang II blood levels. In addition, ang II is pro-arterogeneous by stimulating the growth of the smooth muscles (vessels) [Chobanian A V et al. Renin angiotensin system and atherosclerotic vascular disease. In: Fuster V, Ross R, Topol E J, eds. Atherosclerosis and coronary athery disease. Vol. 1, Philadelphia: Lippincott-Raven, 1996: 237-242; Gibbons G H et al. Vascular smooth muscle cell hypertrophy vs. hyperplasia: autocrine TGF-β1 expression determines growth response to angiotensin II. J. Clin. Invest. 1992; 90: 456-461]. Moreover, ang II also enhances the inflammatory reaction by an increase of the lipoxygenase activity whereby inflammationpromoting mediators are released in increasing amounts.